Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with a notoriously dismal prognosis and is the 4th leading cause of cancer related deaths in the United States. Unfortunately, 80- 85% patients are diagnosed with unresectable, incurable advanced stage tumors putting the median survival at <6 months and the overall 5-year survival at <5%. Therefore, new therapeutic strategies are urgently needed to improve the dismal outcome in PDAC patients. PDAC is characterized by a robust desmoplastic reaction. Desmoplastic reaction endows PDAC with a unique microenvironment that promotes tumor growth, metastasis and resists tumor cells to chemotherapy, collectively resulting in a dismal prognosis. Hence, new treatment strategies are urgently needed to inhibit desmoplasia where nanotechnology could play a pivotal role. Although the mechanism is still not clear and slowly emerging, a number of PCC/PSC secreted factors are recognized to play critical roles facilitating bidirectional crosstalk between PCCs and PSCs that promotes desmoplasia. We demonstrate in the preliminary data that AuNP inhibits proliferation of both PCCs and PSCs and efficiently disrupts the PCC-PSC crosstalk by reducing secretion of a number of critical factors. Therefore, AuNP provides potential opportunities to improve the dismal prognosis in PDAC by simultaneously inhibiting multiple pathways involved in desmoplasia. We also demonstrate in the preliminary data that an AuNP-based targeted drug delivery system efficiently targets and inhibits proliferation of both PCCs and PSCs exploiting overexpression of EGFR in these cells. Since the overproduction of ?-SMA positive PSCs which sometimes account for ~90 % of the total fibrotic mass, depletion of both PSCs and PCCs by AuNP-based targeted drug delivery system is expected to reduce the extent of cross talk and cut down the formation of the huge fibrotic tissue. Decrease in fibrotic mass will allow better drug penetration and delivery, thereby increasing drug sensitivity. Furthermore, nanoconjugates having higher circulation time will soak the fibrotic mass for a longer duration and hence penetrate more efficiently into the fibrotic tissue. Therefore, in the present proposal, we will use a two-pronged approach; 1) disrupting PCC-PSC crosstalk by gold nanoparticle alone and understanding the molecular mechanism, and 2) depleting both PCC and PSC by an AuNP-based targeted drug delivery system to inhibit desmoplasia. We will use three specific aims to accomplish these objectives; Aim 1: Interrogating disruption of PCC-PSC crosstalk by gold nanoparticles; Aim 2: Disrupting PCC-PSC cross-talk tuning pharmacokinetics of a targeted drug delivery system; Aim 3: Improving gemcitabine therapy by reprogramming tumor microenvironment by gold nanoparticle. After decades of ineffective therapeutic strategies against the epithelial component in PDAC, it is only recently realized that the massive stromal tissue is not an innocent bystander but plays critical roles in PDAC progression. Bidirectional crosstalk between PSC and PCC is considered to be the key molecular event that drives desmoplasia. No effective therapeutic strategy currently exists to disrupt PCC-PSC crosstalk. Therefore, the two pronged approach, as proposed in this application, of disrupting PCC-PSC crosstalk (signaling blockade) and abrogating the key components participating in desmoplasia, namely PCCs and PSCs (cellular blockade) is thus highly innovative and provides an exciting opportunity to enhance therapeutic efficacy in PDAC. Successful completion of the aims proposed will help to understand the molecular mechanism of desmoplasia, provide a new and innovative way to inhibit it, and device new therapeutic strategies to enhance drug sensitivity that will inhibit tumor growth, metastasis and improve prognosis in PDAC where practically no effective therapy is currently available.